Aryl boronic acids for treating obesity

ABSTRACT

Disclosed is a phenyl boronic acid compound represented by Structural Formula (I):  
                 
 
     Ar is a substituted or unsubstituted aryl group.  
     Z and Z′ are independently —O—. —NH— or —S—.  
     X is an electron withdrawing group.  
     R is a substituted or unsubstituted straight chained hydrocarbyl group optionally comprising one or more amine, ammonium, ether, thioether or phenylene linking groups and Y is —H, an amine, —[NH—(CH 2 ) q ] r —NH 2 , halogen, —CF 3 , thiol ammonium, alcohol, —COOH, —SO 3 H, —OSO 3 H or phosphonium group covalently bonded to the terminal position of R. Each —NH— in —[NH—(CH 2 ) q ] r —NH 2  is optionally N-alkylated or N,N-dialkylated and —NH 2  in —[NH—(CH 2 ) q ] r —NH 2  is optionally N-alkylated, N,N-dialkylated or N,N,N-trialkylated.  
     q is an integer from 2 to about 10 and r is an integer from 1 to about 5.  
     R 1  and R 1′  are independently —H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or, taken together, are a C2-C5 substituted or unsubstituted alkylene group optionally comprising an amine linking group [—N + (R 1a )—]. Each R 1  is Structural Formula (I) is preferably —H.  
     R 1a  is —H, alkyl, substituted alkyl, phenyl or substituted phenyl.  
     Also disclosed is a method of treating obesity in a subject by administering an effective amount of a compound represented by Structural Formula (I) and a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or diluent.

RELATED APPLICATION(S)

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/302,081, filed Jun. 29, 2001 and U.S. ProvisionalApplication No. 60/359,467, filed Feb. 22, 2002. The entire teachings ofthe above application(s) are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Human obesity is a recognized health problem with approximatelyninety-seven million people considered clinically overweight in theUnited States. Various chemical approaches have been used for treatingobesity. In one such approach, a medicament which inhibits lipases isadministered to the obese patient. Lipases are key enzymes in thedigestive system which break down diglycerides and triglycerides intomonoglycerides and fatty acids. Diglycerides and triglycerides have ahigh caloric content but are not absorbed by the small intestine untilbroken down by the lipases. Therefore, inhibition of lipases within thedigestive system results in a reduction in the absorption of fat andconsequently a decrease in caloric uptake. XENICAL is an example of acommercially available lipase inhibitor that is used for treatingobesity.

[0003] There is still a need, however, for improved lipase inhibitors.For example, administration of lipase inhibitors results in stools witha high fat or oil content from the undigested diglycerides andtriglycerides. Leakage of oil from the stool is an unpleasant sideeffect that often occurs when stools have a high fat or oil content.This condition is referred to as “oily stool” or “leaky stool”. It hasbeen reported in U.S. application Ser. No. 09/166,453 that fat-bindingpolymers, when co-administered with lipase inhibitors, can bind with or“stabilize” the oil and thereby reduce or eliminate the leakage of oilfrom the stool. It would be desirable to develop a single compound whichis both a lipase inhibitor and a fat-binder. In addition, a lipaseinhibitor should be minimally absorbed by the intestines to preventsystemic side-effects. Other desirable features include ease and economyof manufacture.

SUMMARY OF THE INVENTION

[0004] The present invention is directed to novel aryl boronic acids andderivatives thereof which are effective lipase inhibitors (Examples 11and 12). Many of these compounds are readily attached to fat-bindingpolymers comprising alcohol or diol functionalities by means of boronateester, boronate thioester and/or boronamide bonds. These bonds arebelieved to be hydrolyzed in vivo, thereby resulting in the delivery ofa lipase inhibitor and a fat-binding polymer to the gastrointestinaltract. Based on these discoveries, novel aryl boronic acids andderivatives thereof, pharmaceutical compositions comprising these arylboronic acids and derivatives and methods of treating obesity with anovel aryl boronic acid or a derivative thereof are disclosed herein.

[0005] One embodiment of the present invention is a compound representedby Structural Formula (1):

[0006] Z and Z′ are independently —O—, —NH— or —S—. Preferably, Z and Z′are both —O—.

[0007] Ar is a substituted (e.g., monosubstituted or polysubstituted) orunsubstituted aryl group.

[0008] X is an electron withdrawing group.

[0009] R is a substituted or unsubstituted straight chained hydrocarbylgroup optionally comprising one or more amine, ammonium, ether,thioether or phenylene linking groups and Y is —H, an amine,—[NH—(CH₂)_(q)]_(r)—NH₂, halogen, —CF₃, thiol, ammonium, alcohol, —COOH,—SO₃H, —OSO₃H or phosphonium group covalently bonded to the terminalposition of R. Preferably, when Y is —H and R is a straight chainedhydrocarbyl group, then R has from 1 to 30 carbon atoms, preferably 4 to30 carbon atoms, (more preferably from 6 to 30 carbon atoms, even morepreferably from 8 to 30 carbon atoms and even more preferably from 10 to30 carbon atoms). Each —NH— in —[NH—(CH₂)_(q)]_(r)NH₂ is optionallyN-alkylated or N,N-dialkylated and —NH₂ in —[NH—(CH₂)_(q)]_(r)NH₂ isoptionally N-alkylated, N,N-dialkylated or N,N,N-trialkylated.

[0010] R₁ and R₁′ are independently —H, an aliphatic group, asubstituted aliphatic group, an aryl group or a substituted aryl group,or, taken together, a C2-C5 substituted or unsubstituted alkylene groupoptionally comprising an amine linking group [—N⁺(R^(1a))—]. Preferably,R₁ and R₁′ in Structural Formula (I) are both —H.

[0011] R^(1a) is —H, alkyl, substituted alkyl, phenyl or substitutedphenyl.

[0012] q is an integer from 2 to about 10 and r is an integer from 1 toabout five.

[0013] Another embodiment of the present invention is a pharmaceuticalcomposition. The pharmaceutical composition comprises the compounddescribed above and a pharmaceutically acceptable carrier or diluent.Preferably, the pharmaceutical composition comprises an effectiveconcentration of the compound.

[0014] Another embodiment of the present invention is a method forremoving fat from the gastrointestinal tract (or inhibiting uptake offat in the gastrointestinal tract) of a subject in need of suchtreatment (e.g., treating a subject for obesity). The method comprisesthe step of administering an effective amount of the compound describedabove to the subject.

[0015] The aryl boronic acids and aryl boronic acid derivatives of thepresent invention are potent lipase inhibitors. Thus, they are effectivefor the treatment of obesity. Moreover, many of these compounds can beattached to fat-binding polymers. These boron functionalized polymerscan also be used to treat obesity, but have the advantage of not causingthe “oily stools” normally associated with lipase inhibitors. The arylboronic acids and aryl boronic acid derivatives disclosed herein arethus precursors to these improved polymer drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 is a schematic showing the synthesis of4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid chloride (6).

[0017]FIG. 2 is a schematic showing the synthesis of4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)-2,5-difluorophenylboronic acid(11).

[0018]FIG. 3 is a schematic showing the synthesis of (neopentylglycolato)4-(14′-trimethylammonium-3′-thia-1′-ketotridecyl)-2,5-difluorophenylboronateester chloride (14).

[0019] FIGS. 4A-4F are a compilation of structural formulas representingboronic acids of the present invention. R in FIG. 4 is a C12 straightchained alkyl group.

DETAILED DESCRIPTION OF THE INVENTION

[0020] The invention is described below with respect to aryl boronicacids and aryl boronate esters, i.e., wherein Z and Z′ are both —O—. Itis to be understood that these descriptions apply to the correspondingboronamides and boronate thiesters, i.e., wherein one or both of Z andZ′ are —NH— or —S—.

[0021] Ar in Structural Formula (I) is substituted or unsubstituted. Aris “substituted” when it comprises at least one substituent in additionto the boronic acid group and the —X—R—Y group. Suitable substituentsare as described below for aryl groups.

[0022] —X— is an electron withdrawing group. As used herein, an“electron withdrawing group” is a substituent which results in a phenylring that has less electron density when the group is present than whenit is absent. Electron withdrawing groups have a Hammet sigma valuegreater than one (see, for example, C. Hansch, A. Leo and D. Hoeckman,“Exploring QSAR Hydrophobic, Electronic and Steric Constants”, AmericanChemical Society (1995), pages 217-32) Examples of suitable values for Xinclude —CHZ—, —CZ₂—, —COO—, —CON(R^(1b))—, —CO— or —SO₂—. Othersuitable values of X include —S(O)— and —S(O)₂O—. Z is a halogen andR^(1b) is —H, alkyl or substituted alkyl (preferably —R—Y). In thecompounds of the present invention, Phenyl Ring A is preferablysubstituted with one or more electron withdrawing groups in addition to—X—. Suitable examples include halogens, —NO₂ and —CN; fluorine is apreferred example.

[0023] A “straight chained hydrocarbyl group” is an alkylene group,i.e., —(CH₂)_(x)— where x is a positive integer (e.g., from 1 to about30), preferably between 6 and about 30, more preferably between about 6and about 15. A “linking group” refers to a functional group whichreplaces a methylene in a straight chained hydrocarbyl. Examples ofsuitable linking groups include an alkene, alkyne, phenylene, ether(—O—), thioether (—S—), amine [—N⁺(R^(a))—] or ammonium[—N⁺(R^(a)R^(b))—]. R^(a) and R^(b) are independently —H, alkyl,substituted alkyl, phenyl, substituted phenyl, or, taken together withthe nitrogen atom to which they are bonded, a non-aromatic,nitrogen-containing heterocyclic group. Preferably, R^(a) and R^(b) arenot —H. More preferably, R^(a) and R^(b) are both alkyl groups and evenmore preferably, both methyl. R^(a) and R^(b) can be the same ordifferent, but are preferably the same.

[0024] The terms “terminal position” or “terminus” refer to themethylene carbon of the straight chained hydrocarbyl group most distantfrom Ar. Substituents at the terminal position of a straight chainedhydrocarbyl group are referred to herein as “terminal substituents”. Asnoted above, a number of compounds of the present invention have anamine (—NR^(c)R^(d)) or ammonium (—N⁺R^(c)R^(d)R^(e)) group as aterminal substituent of the hydrocarbyl group represented by R. R^(c),R^(d) and R^(e) in an ammonium group are independently —H, alkyl,substituted alkyl, phenyl, substituted phenyl, or, taken together withthe nitrogen atom to which they are bonded, a nitrogen-containing,non-aromatic heterocyclic group. Preferably, R^(c), R^(d) and R^(e) arenot —H. More preferably, R^(c), R^(d) and R^(e) are all alkyl groups(i.e., a trialkylammonium group) and even more preferably, all methyl(i.e., a trimethylammonium group). R^(c), R^(d) and R^(e) can be thesame or different, but are preferably all the same.

[0025] In one example Y is selected such that YH is a small moleculepolyamine (H—[NH—(CH₂)_(q)]_(r)—NH₂) such as spermine, spermidine,1,2-diaminoethane, 1,3-diaminopropane or 1,4-diaminobutane. Optionally,one or more of the secondary amine can optionally be N-alkylated orN,N-dialkylated; the primary amine is optionally N-alkylated,N,N-dialkylated or N,N,N-trialkylated.

[0026] A “substituted hydrocarbyl group” has one or more substituentsbonded at one or more positions other than at the terminus. Suitablesubstituents are those which do not significantly lower the lipaseinhibiting ability or fat binding ability of the polymer, for example,do not lower either activity by more than a factor of about two.Examples of suitable substituents include C1 -C3 straight chained orbranched alkyl, C1 -C3 straight chained or branched haloalkyl, —OH,halogen (—Br, —Cl, —I and —F), —O(C1-C3 straight chain or branchedalkyl) or —O(C1 -C3 straight chain or branched haloalkyl).

[0027] In a preferred embodiment, the compound of the present inventionis represented by Structural Formula (II):

[0028] Phenyl Ring A is substituted or unsubstituted. Phenyl Ring A is“substituted” when it comprises at least one substituent in addition tothe boronic acid group and the —X—R—Y group. Suitable substituents areas described below for aryl groups.

[0029] R, R₁, R′₁, X and Y in Structural Formula (II) are as describedfor Structural Formula (I). Preferably, Y—R—X— is para to —B(OR₁)(OR′₁).

[0030] In a more preferred embodiment, the compound of the presentinvention is represented by Structural Formula (III):

[0031] Phenyl Ring A, R and Y in Structural Formula (III) are asdescribed above for Structural Formula (II). Phenyl Ring A is preferablysubstituted with zero, one or more independently selected electronwithdrawing groups represented by R₂.

[0032] R in Structural Formulas (II) and (III) is a substituted orunsubstituted straight chained hydrocarbyl group optionally comprisingone or more ether, thioether, phenylene, amine, or ammonium linkinggroups. Preferred linking groups for R in Structural Formulas (II) and(III) are ether or thioether. Alternatively, R in Structural Formulas(II) and (III) is —CH₂—O[—(CH₂)_(p)O]_(m)—(CH₂)_(p)— or—CH₂—S[—(CH₂)_(p)O]_(m)—(CH₂)_(p)—; p is 2 or 3; and m is an integerfrom 1-8.

[0033] Y in Structural Formulas (II) and (III) is preferably an amine orammonium group covalently bond to the terminal position of R, morepreferably a trialkylammonium group bonded to the terminal position of Rand even more preferably a trimethylammonium group bonded to theterminal position of R.

[0034] In a more preferred embodiment, the compound of the presentinvention is represented by Structural Formulas (IV) and (V):

[0035] Phenyl Ring A in Structural Formulas (IV) and (V) is as describedfor Structural Formulas (II)-(III).

[0036] Y in Structural Formulas (IV) and (V) is a trialkylammoniumgroup. n is an integer from about 6 to about 30, preferably from about 6to about 15.

[0037] Preferably in Structural Formulas (IV) and (V), Y istrimethylammonium, Phenyl Ring A is substituted with one or two fluorinegroups and n is as defined above. Examples of suitable substitutionpatterns for Phenyl Ring A include 3-fluoro and 2,5-difluoro, whereinthe carbon bonded to boron is considered to be carbon one.

[0038] Also included in the present invention are boronate esters of theboronic acids represented by Structural Formulas (III)-(V). A boronateester is obtained by replacing one or both boronic acid hydrogen atomswith R₁, as described in Structural Formulas (I) and (II). It isbelieved that boronate esters are hydrolyzed in the gastrointestinaltract to form boronic acids, which then act as lipase inhibitors.

[0039] Also included in the present invention are the boronamides orboronate thioesters corresponding to the boronate esters described inthe previous paragraph. The boronamide or boronate thioester is obtainedby independently replacing one or both boronate ester oxygen atoms with—S— or —NH—.

[0040] As used herein, aliphatic groups include straight chained,branched or cyclic C1-C30 (preferably C1-C15) hydrocarbons which arecompletely saturated or which contain one or more units of unsaturation.Preferred aliphatic groups are completely saturated and acyclic, i.e.,straight chained or branched alkyl groups or alkylene groups. Suitablesubstituents for an aliphatic group are those which do not significantlylower the lipase inhibiting ability of the compound, for example, do notlower either activity by more than a factor of about two. Examplesinclude —OH, halogen (—Br, —Cl, —I and —F), —O(R′), —O—CO—(R′), —CN,—NO₂, —COOH, ═O, —NH₂, —NH(R′), —N(R′)₂, —COO(R′), —CONH₂, —CONH(R′),—CON(R′)₂, —SH and —S(R′). Each R′ is independently an alkyl group or anaryl group. A substituted aliphatic group can have more than onesubstituent.

[0041] Aryl groups include carbocyclic aromatic groups such as phenyland naphthyl, heteroaryl groups such as imidazolyl, thienyl, furanyl,pyridyl, pyrimidy, pyranyl, pyrazolyl, pyrazinyl, thiazole, oxazolyl andfused polycyclic aromatic ring systems in which a carbocyclic aromaticring or heteroaryl ring is fused to one or more other heteroaryl rings(e.g., benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazole,benzooxazole, benzimidazole and quinolinyl). Suitable substituents foran aryl group are those which do not significantly lower the lipaseinhibiting ability of the compound, for example, do not lower eitheractivity by more than a factor of about two. Examples include alkyl,halogenated alkyl, —OH, halogen (—Br, —Cl, —I and —F), —O(R′),—O—CO—(R′), —CN, —NO₂, —COOH, —NH₂, —NH(R′), —N(R′)₂, —COO(R′), —CONH₂,—CONH(R′), —CON(R′)₂, —SH and —S(R′). Each R′ is independently an alkylgroup or an aryl group. A substituted aryl group can have more than onesubstituent.

[0042] Non-aromatic nitrogen-containing, heterocyclic rings arenon-aromatic carbocyclic rings which include at least one nitrogen atomand, optionally, one or more other heteroatoms such as oxygen or sulfurin the ring. The ring can be five, six, seven or eight-membered.Examples include morpholino, thiomorpholino, pyrrolidinyl, piperazinyland piperidinyl.

[0043] Also included in the present invention are pharmaceuticallyacceptable salts of the disclosed compounds. For example, compoundswhich have acid functional groups can be present in the anionic, orconjugate base, form, in combination with a cation. Suitable cationsinclude alkaline earth metal ions, such as sodium and potassium ions,alkaline earth ions, such as calcium and magnesium ions, andunsubstituted and substituted (primary, secondary, tertiary andquaternary) ammonium ions. Compounds which have basic groups such asamines can be present in a protonated form together with apharmaceutically acceptable counter anion, such as chloride, bromide,acetate, formate, citrate, ascorbate, sulfate or phosphate. Similarly,ammonium groups comprise a pharmaceutically acceptable counteranion.Boronic acid groups can react with anions such as sodium or potassiumhydroxide, alkoxide or carboxylate to form a salt such as —B⁻(OH)₃Na⁺,—B⁻(OH)₃K⁺, —B⁻(OH)₂(OCH₃)Na⁺, —B^(−(OH)) ₂(OCH₃)K⁺,—B⁻(OH)₂(OCOCH₃)Na⁺, —B⁻(OH)₂(OCOCH₃)K⁺, and the like.

[0044] A “subject” is preferably a mammal, such as a human, but can alsobe a companion animal (e.g., dogs, cats, and the like), farm animals(e.g., cows, sheep, pigs, horses, and the like) or laboratory animals(e.g., rats, mice, guinea pigs, and the like) in need of treatment forobesity.

[0045] The compounds of the present invention are suitable as amedicament for promoting weight reduction in subjects because theyinhibit lipases in the gastrointestinal tract. As such, they areadministered in a manner suitable for reaching the gastrointestinaltract during digestion. They are therefore preferably administeredorally as soon as up to about one hour prior to a meal and as late as upto about one hour subsequent to a meal. Alternatives modes ofadministration are also possible, including rectal, nasal, pulmonary andtopical administration.

[0046] The compounds of the present invention are administered toinhibit of uptake of fat in the gastrointestinal tract (or to promoteremoval of fat from the gastrointestinal tract). Thus, they can be alsobe advantageously used to in the treatment or one or more of thefollowing conditions: obesity, Type II (non-insulin-dependent) diabetesmellitus, impaired glucose tolerance, hypertension, coronary thrombosis,stroke, lipid syndromes, hyperglycemia, hypertriglyceridemia,hyperlipidemia, sleep apnea, hiatal hernia, reflux esophagisitis,osteoarthritis, gout, cancers associated with weight gain, gallstones,kidney stones, pulmonary hypertension, infertility, cardiovasculardisease, above normal weight, and above normal lipid levels; or wherethe subject would benefit from reduced platelet adhesiveness, weightloss after pregnancy, lowered lipid levels, lowered uric acid levels, orlowered oxalate levels. A subject with one or more of these conditionsis said to be “in need of treatment” with an agent that inhibitsabsorption of fat from the gastrointestinal tract.

[0047] The compounds can be administered to the subjects in conjunctionwith an acceptable pharmaceutical carrier as part of a pharmaceuticalcomposition for treatment of obesity. Formulations vary according to theroute of administration selected, but are typically capsules, tablets orpowder for oral administration. Solutions and emulsions are alsopossible. Suitable pharmaceutical carriers may contain inert ingredientswhich do not interact with the compound. Standard pharmaceuticalformulation techniques can be employed, such as those described inRemington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa. Methods for encapsulating compositions (such as in a coating of hardgelatin or cyclodextran) are known in the art (Baker, et al.,“Controlled Release of Biological Active Agents”, John Wiley and Sons,1986).

[0048] An “effective amount” is the quantity of compound which resultsin a greater amount of weight reduction over a period of time duringwhich a subject is being treated with the aryl boronic acid drug forobesity compared with the corresponding time period in absence of suchtreatment. Typical dosages range from about 5 mg/day to about 10grams/day, preferably from about 5 mg/day to about 5 grams/day. Thecompound can be administered alone or in a pharmaceutical compositioncomprising the compound, an acceptable carrier or diluent and,optionally, one or more additional drugs, typically one or moreadditional drugs used for weight reduction (e.g., XENICAL or MERIDIA).The precise amount of drug being administered to a subject will bedetermined on an individual basis and will depend on, at least in part,the subject's individual characteristics, such as general health, age,sex, body weight and tolerance to drugs, and the degree to which thesubject is overweight and the amount of weight reduction sought.

[0049] An “effective concentration” is the concentration of compoundpresent in a pharmaceutical composition which, when divided into a unitdosage form, provides an effective amount of the compound.

[0050] The aryl boronic acid compounds of the present invention can alsobe reacted to form boronate esters with pharmaceutically acceptablepolymers having free alcohol or diol groups and administered as apolymer drug. Reactions for forming boronate ester bonds are well knownin the art and include refluxing the boronic acid and diol in anappropriate solvent (e.g., alcohol, toluene, methylene chloride,tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO)). Alternatively, anaryl boronic acid can be to a polymer having free alcohol or diol groupsby means of a transesterification reaction, as described in D. H. Kinderand M. M. Ames, Journal of Organic Chemistry 52:2452 (1987) and D. S.Matteson and R. Ray, Journal of American Chemical Society 102:7590(1980), the entire teachings of which are incorporated herein byreference.

[0051] The boronate ester of these polymer drugs is believed to behydrolyzed in the gastrointestinal tract to release the aryl boronicacid, which can then act to inhibit lipase enzymes. Preferably, thepolymer is a fat-binding polymer. After hydrolysis of the aryl boronateester to release the aryl boronic acid, the fat-binding polymer is thenavailable to absorb the diglyercides and triglycerides which remainundigested as a result of inhibition of the lipase enzymes by thereleased aryl boronic acid. The undesired side-effect of “oily stools”is thereby minimized or eliminated through the use of these polymerdrugs. “Fat-binding polymers” are polymers which absorb, bind orotherwise associate with fat thereby inhibiting (partially orcompletely) fat digestion, hydrolysis, or absorption in thegastrointestinal tract and/or facilitate the removal of fat from thebody prior to digestion. The fat-binding polymers generally comprise oneor more fat-binding regions. “Fat-binding regions” include a positivelycharged region and, optionally, a hydrophobic region, or a region whichis both positively charged and hydrophobic. The fat-binding region has apositive charge when the region comprises an ionic group such as aquaternary amine or an atom, for example, the nitrogen of an amine, thatpossesses a positive charge under conditions present in thegastrointestinal tract. The attachment of artl boronic acid lipaseinhibitors to fat-binding polymers and the use of these polymers asanti-obesity drugs are described in the co-pending U.S. ProvisionalApplication Serial No.: 60/302,221, entitled “Aryl BoronateFunctionalized Polymers for Treating Obesity,” filed on Jun. 29, 2001,and U.S. Provisional Application Serial No.: 60/359,473, entitled “ArylBoronate Functionalized Polymers for Treating Obesity,” filed Feb. 22,2002. The entire teachings of this application are incorporated hereinby reference.

[0052] The preparation of representative phenyl boronic acid compoundsis described in Examples 1-10 and shown schematically in FIGS. 1-3. Theperson of ordinary skill in the art will be able to select suitablestarting materials to obtain the desired aryl boronic acid and, whencarrying out these reactions with different starting materials, tomodify reaction conditions, if necessary, using no more than routineexperimentation. For example, the 4-bromoacetophenone in FIG. 2(Compound 7) can be replaced with any suitable aryl compound substitutedwith bromine or iodine and acetyl. For example,2-Acetyl-5-bromothiophene is commercially available from the AldrichChemical Co., Milwaukee, Wis. The length of the hydrocarbyl group in thearyl boronic acids can be varied according to the length of thel,ω-alkanethioalcohol.

[0053] Representative boronic acids of the present invention that havebeen prepared according to methods described in the examples are shownin FIG. 4.

[0054] The invention is further illustrated by the following exampleswhich is not intended to be limiting in any way.

EXEMPLIFICATION Example 14-(14′-Trimethylammonium-3′-Thia-1′-Ketotetradecyl)-3-FluorophenylboronicAcid Chloride (6)

[0055] The synthesis of Compound (6) is shown out schematically inFIG. 1. A detailed description of the procedure is provided below.

[0056] Step 1. Synthesis of 4-acetyl-3-fluorophenylboronic acid (1).

[0057] An oven-dried, 3-liter, 3-necked, round-bottomed flask (fittedwith a nitrogen inlet, addition funnel, and overhead stirrer) wascharged with 50 grams (0.25 mole) of 4-cyano-3-fluorophenyl bromide.Anhydrous tetrahydrofuran (200 milliliters) was added to the flaskresulting in a clear solution. The solution was cooled to 0° C. using anice bath. At this temperature, 125 milliliters of 3.0 M solution ofCH₃MgBr in ether (1.5 equivalents, 0.375 mole) was added slowly to thereaction flask using an addition funnel. The reaction mixture wasallowed to slowly warm up to room temperature and was stirred for 48hours. Thin layer chromatography (TLC) indicated the starting materialwas consumed. After 48 hours, the reaction was cooled down to −78° C.using an isopropanol/dry ice bath. At —78° C., 50 milliliters of 10.0 Msolution of butyllithium in hexane (2.0 equivalents, 0.5 mole) was addedto the reaction mixture with continuing stirring. An additional 400milliliters of THF was added to ensure that reaction mixture washomogeneous and was stirring well. The reaction mixture was stirred at—78° C. for 3 hours. To the reaction mixture was added 170 millilitersof trimethylborate (6.0 equivalents, 1.5 mole) slowly using an additionfunnel and the temperature was maintained at —78° C. While stirring, thereaction mixture was allowed to warm up to room temperature overnight.The progress of the reaction was monitored by TLC. After cooling thereaction mixture to 0° C. (using an ice bath) the contents weretransferred into a 5 liter beaker. The flask was rinsed with 100milliliters of methanol and the washing was combined with the reactionmixture. To the reaction mixture, 500 milliliters of 1 N HCl was slowlyadded. Subsequently, the pH of the mixture was brought to 4 by theaddition of concentrated HCl. The reaction mixture was stirred for 3hours. The organic solvent was removed by rotary evaporator. Theconcentrated aqueous content was extracted with ether (250milliliter×6). The combined organic layer was washed with brine solution(200 milliliter×2) and was dried over MgSO₄. After filtration, ether wasremoved by rotary evaporator. The residue was recrystallized from hotwater yielding an off white solid. Yield: 22 grams (50%).

[0058] Step 2. Synthesis of 4-(2′-bromoacetyl)-3-fluorophenylboronicacid (2).

[0059] An oven-dried, 500-milliliter, 3-necked, round-bottomed flask wascharged with 5 grams (27.4 millimole) of 4-acetyl-3-fluorophenyl boronicacid and 25 milliliters of methanol under a nitrogen atmosphere. Thesolution was cooled to 0° C. using an ice bath. To this solution wasadded 0.2 milliliters (0.55 equivalents) of glacial acetic acid. In a100 milliliters Erlermeyer flask was taken 1.27 milliliters (3.95 grams,24 millimole, 0.9 equivalents) of elemental bromine dissolved in 4milliliters of cold methanol. The bromine solution was added dropwise tothe above solution at 0° C. using an addition funnel. With the additionof Br₂, the solution slowly turned light orange and finally to darkorange when addition was complete. After about 5-6 hours, the progressof the reaction was monitored by NMR. Depending on the progress ofreaction, another 10-20 mole % of bromine was added after cooling thesolution to 0° C. Total reaction time was approximately 24 hours.

[0060] After completion of the reaction, the solvent was removed usingrotary evaporator. The residue was dissolved in 200 milliliters of ethylacetate. It was washed with deionized water (50 milliliters×3) and withbrine (50 milliliters×2). The organic layer was collected and dried overanhydrous sodium sulfate for 1 hour. The solution was filtered and thesolvent was removed using rotary evaporator. The residue wasrecrystallized from hot ethyl acetate. Yield=7 grams (97%).

[0061] Step 3. Synthesis of4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronic acid(3).

[0062] An oven-dried, 500-milliliter, three-necked, round-bottomed flaskwas charged with 5 grams (19.15 millimole) of4-(2′-bromoacetyl)-3-fluorophenylboronic acid (2) and 50 milliliters ofanhydrous THF. The solution was flushed with N₂ for at least 30 minutes.To this solution was added 3.9 grams (19.15 millimole, 1 equivlalent) of11-mercaptoundecanol. While stirring under N₂, 6.62 milliliters (38.3millimole, 2 equivalents) of diisopropylethylamine was added slowly. Thereaction mixture was stirred at room temperature for 24 hours undernitrogen atmosphere. The progress of the reaction was monitored by TLCand NMR (after washing up the aliquot with 1N HCl). If the reaction wasnot complete, additional (as required) 11-mercaptoundecanol was addedand the reaction was allowed to proceed for another 24 hours. Aftercompletion of the reaction, the solvent was evaporated. The residue wasdissolved in 200 milliliters of ethyl acetate and was washed with water(50 milliliters×3), 1 N HCl (50 milliliters×3) and with brine (50milliliters×2). The organic layer was dried over an anhydrous sodiumsulfate for 1 hour. After filtration, the solvent was removed by rotaryevaporator. The residue was recrystallized from ethyl acetate. Yield: 5grams (72%).

[0063] Step 4. Synthesis of neopentyl glycol protected4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronic acid(4).

[0064] An oven-dried, 500-milliliter, 3-necked, round-bottomed flask wascharged with 5 grams (13 millimole) of 3 as prepared above. Addition of100 milliliters of anhydrous dichloromethane produced a dispersion.While stirring, 1.42 grams (13.65 millimoles, 1.05 equivalents) ofneopentylglycol was added to this dispersion. After few minutes a clearsolution was obtained. The stirred reaction mixture was heated toreflux. A chiller and a Dean Stark apparatus were used to remove thedichloromethane-water azeotrope. The heating continued for about 3hours.

[0065] At the end of reflux, the reaction mixture was allowed to cool toroom temperature and the solvent was removed using a rotary evaporator.Anhydrous toluene (50 milliliters) was added to the residue and thetoluene was removed using a rotary evaporator. This toluene treatmentprocess was repeated once more. The residue was dissolved in 5milliliters of dichlormethane, and hexane was added to this solution(with stirring) until cloudiness appeared (about 150 milliliters). Thesolution was kept in the freezer for recrystallizaton. After few hoursthe product crystallized and was isolated by filtration. Yield=5.13grams (87%).

[0066] Step 5. Synthesis of neopentyl glycol protected4-(14′-bromo-3′-thia-1-ketotetradecyl)-3-fluorophenylboronic acid (5).

[0067] The reaction was carried out under N₂ atmosphere.

[0068] An oven-dried, 500-milliliter, 3-necked, round-bottomed flask wascharged with 5.13 grams (11.33 millimole) of the neopentyl glycolprotected boronic acid (4) and 50 milliliters of anhydrousdichloromethane under a nitrogen atmosphere. To this solution was added7.52 grams (22.67 millimole, 2 equivalents) of carbon tetrabromide. Theresulting solution was allowed to stir at 0° C. using an ice bath. Asolution of 5.95 grams (22.67 millimole, 2 equivalents) oftriphenylphosphine dissolved in 10 milliliters of anhydrousdichloromethane was added slowly to the reaction mixture using anaddition funnel. The reaction mixture was stirred at 0° C. and wasallowed to slowly warm to room temperature. Total reaction time wasabout 24 hours. At the end of the reaction 20 milliliters of methanolwas added to the reaction mixture. After stirring for 1 hour, thesolvent was removed by rotary evaporator. The residue was treated with200 milliliters of diethyl ether and stirred for 30 minutes. The mixturewas filtered and the solvent was removed under reduced pressure. Theresidue was given another ether treatment in the above manner and thesolvent was removed. The resulting residue was flash chromatographedusing hexane/ethyl acetate (98/2) as the solvent system. After removalof the solvent the product was isolated as an off-white solid. Yield=4.3grams (74%).

[0069] Step 6. Synthesis of4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid chloride (6).

[0070] A 100-milliliter, round-bottomed flask was charged with 4.3 grams(8.3 millimole) of boronic acid derivative (5) and 40 milliliters ofethanol. To this solution was added 40 milliliters of aqueoustrimethylamine solution (40%, Aldrich). The reaction mixture was stirredat 70° C. for 24 hours. After cooling to room temperature, the ethanolwas removed by rotary evaporator. The remaining aqueous solution wascooled to 0° C. and 180 milliliters of 1 N HCl was added slowly into thestirring solution. If precipitation occurs, some methanol is added untila clear solution forms. After stirring for 5 hours, the solution(turbid) was extracted with chloroform (3×200 milliliters). Organiclayers were collected and dried over sodium sulfate. The chloroform wasevaporated and the residue was dissolved in methanol (20 milliliters).Sodium chloride solution (10% w/w, 200 milliliters) was added to themethanol solution and stirred for 1 hour. At this point, the organicsolvent was removed using rotary evaporator and compound was extractedfrom aqueous solution with chloroform (3×200 milliliters). Organiclayers were collected and dried over sodium sulfate. After filtration,the solvent was removed using rotary evaporator. The residue was addedto 600 milliliters of ether and the mixture was kept in the freezer for3 hours. The solvent was decanted to isolate the product. Yield=2 grams.

Example 2 Synthesis of2,5-Difluoro-4-(14′-Hydroxy-3′-Thia-1′-Ketotetradecyl)Phenylboronic Acid(11)

[0071] The synthesis of Compound (11) is shown out schematically in FIG.2. A detailed description of the procedure is provided below.

[0072] Step 1—Synthesis of 4-bromo-2,5-difluoroacetophenone (7)Anhydrous aluminum chloride was mixed (5 grams, 37.5 millimoles, 2.4equivalents) with 1-bromo-2,5 difluorobenzene in a dry, round-bottomflask blanketed with nitrogen and fitted with a condenser. The mixturewas heated to 60° C. and acetyl chloride (1.7 milliliters, 23.3millimole, 1.5 equivalents) was added by syringe. The wet yellow solidchanged then into a scarlet solution and was heated at 90° C. for 1hour. The reaction mixture was poured onto 38 grams of ice, HCl wasadded (3 milliliters, 37% concentration) and the mixture was extractedwith ether. The crude material was dried over magnesium sulfate andevaporated down. The crude material was purified by columnchromatography or distilled. The product (1.2 grams, 31%) was obtainedas a yellow oil.

[0073] Step 2—Synthesis of neopentyl glycol protected4-acetyl-2,5-difluorofluorophenylboronic acid (8).

[0074] Dichloro [(1,1′-bis(diphenylphosphino)ferrocene] palladium (11)dichloromethane adduct (1.7 grams, 2.3 millimole, 5% mole) was added toa suspension of 4-bromo-2,5 difluoroacetophenone (7) (10.5 grams, 46.38millimole, 1 equivalents), bis(neopentyl glycolato)diboron (12.57 grams,55.65 millimole, 1.2 equivalents) and potassium acetate (13.66 grams,139.13 millimole, 3 equivalents) in anhydrous DMSO (100 milliliters).The suspension was heated to 80° C. under nitrogen for 1 hour (J. Org.Chem. 60:7508 (1995)). After 1 hour, TLC showed full conversion of thestarting material and the reaction mixture was allowed to cool down andextracted with toluene, washed three times with water and dried overmagnesium sulfate. Flash column chromatography was used to purify thecrude (4.2 grams, 32%).

[0075] Step 3—Synthesis of neopentyl glycol protected4-(2′-bromoacetyl)-2,5-difluorophenylboronic acid (9)

[0076] The boronic ester (8) (4.1 grams, 14.93 millimole, 1 equivalent)was dissolved in methylene chloride (50 milliliters) and cooled down to−10° C. Acetic acid (0.82 milliliters, 14.32 millimole, 1 equivalent)was added, followed by bromine (0.7 milliliters, 13.4 millimole, 0.9equivalents) and the reaction was warmed up to room temperature. Afterstirring for two hours the reaction mixture was diluted with moremethylene chloride and washed once with water and once with brine. Thecrude was dried over magnesium sulfate, evaporated down and used in thenext step without further purification.

[0077] Step 4—Synthesis of neopentyl glycol protected2,5-difluoro-4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid(10)

[0078] Crude Compound (9) (14.93 millimole) was dissolved in anhydrousmethanol (50 milliliters) and nitrogen gas was bubbled into the solutionfor 20 minutes to degas the mixture. 11-mercaptoundecanol (3.1 grams,14.93 millimole, 1 equivalent) was added to the reaction and thesolution was allowed to stir under nitrogen for five minutes beforeadding anhydrous diisopropylamine (5.2 milliliters, 29.9 millimole, 2equivalents). The reaction was left to stir under nitrogen overnight andthe crude was worked up by evaporating the reaction mixture to drynessand re-dissolving it in a 10% mixture of THF in ethyl acetate (100milliliters). This organic layer was then washed with 200 milliliters ofwater and the aqueous layer was separated and washed with three newfractions of the same THF/ethyl acetate mixture (100 milliliters each).The crude organic layers were combined, dried over magnesium sulfate andevaporated down. Flash chromatography was used to purify the crude andan off white solid was obtained (3.5 grams, 50%).

[0079] Step 5—Synthesis of2,5-difluoro-4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid(11).

[0080] De-protection of the neopentyl group in Compound (10) to giveCompound (11) was carried out by dissolving Compound (10) in methanoland adding a few drops of HCl. After stirring for about an hour thecrude product was concentrated on a rotary evaporator and the finalcompound was recrystallized from hot ethyl acetate.

Example 3 Synthesis of2,5-Difluoro-4-(13′-Trimethylamonium-3′-Thia-1′-Ketotridecyl)Phenyl(Neopentyl Glycolato) Boron Chloride (14)

[0081] The synthesis of Compound (14) is shown schematically in FIG. 3.A detailed description of the procedure is provided below.

[0082] Step 1—Synthesis of 10-bromodecyltrimethylammonium bromide

[0083] 1,10-Dibromodecane (20 grams, 66.7 mmoles) and THF (100milliliters) were placed in a 500-mL, three-necked flask. The solutionwas cooled to 0° C. with an ice-water bath. Anhydrous trimethylamine (3grams, 50.8 mmoles) was added to the mixture by slowly bubblingtrimethylamine gas for about 15 minutes. Then the reaction mixture wasallowed to warm to room temperature and stirred at room temperatureovernight. The solid material was filtered and washed with THF (5×30milliliters). After drying in vacuo overnight, 12.5 grams (34.82 mmoles,69% based on the amine used) of the product was obtained as a whitesolid.

[0084] Step 2—Synthesis of 10-mercaptodecy trimethylammonium bromide

[0085] 10-Bromodecyltrimethylammonium bromide (10 grams, 27.9 mmoles) in50 mL of methanol was placed in a 250-milliliter, three-necked flask.The mixture was degassed vigorously by bubbling nitrogen for 30 min.Potassium thioacetate (3.8 grams, 33.5 mmoles, 1.2 equivalents) wasadded to the reaction mixture. The mixture was heated at 50° C. for 12hours under nitrogen. The reaction mixture was cooled to 0° C. with anice-water bath, degassed sodium hydroxide (50%, 2.7 grams, 33.5 mmoles,1.2 equivalents) was added, and the mixture was stirred for 1 h at roomtemperature. The mixture was cooled to 0° C., and degassed concentratedhydrochloride acid was added dropwise to achieve pH 2. Degassed methanol(100 milliliters) was added to the reaction mixture, followed by theaddition of 40 grams of magnesium sulfate. Magnesium sulfate wasfiltered off and washed with methanol. The methanol solution wasconcentrated to about 20 milliliters, and ether (300 milliliters) wasadded to the mixture. The flask was sealed and placed in a freezer.Product was crystallized out as a white solid. The product was filtered,washed with ether, and dried in vacuo. Product (7.5 grams, 24.0 mmoles,86%) was obtained as a white hydroscopic solid.

[0086] Step 3—Synthesis of2,5-difluoro-4-(13′-trimethylammonium-3′-thia-1′-ketotridecyl)fluorophenylboronicacid bromide

[0087] 4-(2′-Bromoacetyl)-2,5-difluorophenyl (neopentyl glycolato) boron(Compound 9) (1 millimole) was dissolved in anhydrous methanol (10milliliters) and nitrogen gas was bubbled into the solution for 20minutes to degas the mixture. 10-mercaptodecyltrimethylammonium bromide(0.19 grams, 0.8 millimole, 0.8 equivalents) was added to the reactionand the solution was stirred under nitrogen for five minutes beforeadding anhydrous diisopropylamine (0.14 milliliters, 1 millimole, 1equivalent). The reaction was stirred under nitrogen overnight and,after concentration on a rotary evaporator, purified by preparativereversed phase PLC.

Example 4 Synthesis of4-(14′-Trimethylammonium-3′-Thia-1′-Keto-Tetradecyl)Phenylboronic AcidChloride

[0088]

[0089] Step 1. Synthesis of 4-(2′-Bromoacetyl)phenylboronic acid.

[0090] An oven-dried, two liter, three-necked, round-bottomed flask wascharged with 4-acetyl-phenylboronic acid (20 grams, 0.152 mole). Whilestirring, 175 ml of THF were added to the reaction mixture, followed by700 ml of chloroform. To the resulting solution was added 5 ml ofglacial acetic acid. A chloroform solution of bromine (prepared bydissolving 7 ml of bromine in 30 ml of chloroform) was added slowly tothe reaction mixture at about 5° C. After the completion of the additionof bromine, the reaction mixture was allowed to warm to room temperatureand stirred at room temperature for 16 hours. The solvent was removed byrotary evaporation and the residue was dissolved in 1 liter of ethylacetate. The resulting solution was extracted with deionized water(3×200 ml) and brine (2×100 ml). The organic layer was dried overanhydrous sodium sulfate for 1 hour. The solution was then filtered andconcentrated to about ⅓ of its volume. The resulting solution was keptin a freezer to crystallize the product. The solid was filtered to givean off white solid. Yield=16 grams

[0091] Step 2. 4-( 14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronicacid.

[0092] A 500-ml, three-necked, round-bottomed flask was charged with 15grams of 4-(2′-bromoacetyl)phenylboronic acid and 300 ml of anhydrousTHF. While stirring under a nitrogen atmosphere, 12.26 grams of11-mercaptoundecanol were added to the reaction mixture, followed by32.35 ml of diisopropylethylamine. The reaction mixture was stirredunder a nitrogen atmosphere for 48 hours. After removing the solvent byrotary evaporation, the residue was dissolved in 500 ml of ethylacetate. The organic phase was washed with deionized water (2×200 ml),1N HCl (3×200 ml), deionized water (200 ml), and brine (200 ml). Thewashed organic layer was then dried over anhydrous sodium sulfate for 15minutes. The solution was filtered and concentrated to one fourth of itsvolume. While stirring, hexane was added slowly to this solution untilpermanent cloudiness appeared. The solution was kept in the freezer tocrystallize the product. After filtration, the residue was dried undervacuum at room temperature yielding 17 grams of the product as anoff-white solid.

[0093] Step 3. Synthesis of (neopentyl glycolato)4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronate ester.

[0094] An oven-dried, 500 ml, 3-necked, round-bottomed, flask wascharged with 5 grams of 4-(14′-hydroxy-3-thia-1-keto)tetradecylphenylboronic acid and 100 ml of anhydrous dichloromethane. Whilestirring, 1 gram of neopentylglycol was added and the reaction mixturewas heated to reflux with stirring. The heating continued for 3 hourswith azeotropic distillation of water. The reaction mixture was allowedto cool to room temperature and the solvent was removed using a rotaryevaporator. Anhydrous toluene (50 ml) was added to the residue and thetoluene was removed using a rotary evaporator. This toluene treatmentprocess was repeated once more. The residue was dissolved in 5 ml ofdichloromethane and hexane was added to this solution (with stirring)until cloudiness appeared. The solution was kept in the freezer forrecrystallizaton. The product was isolated by filtration, and upondrying, 4.8 grams of the compound was obtained as an off-white solid.

[0095] Step 4. Synthesis of (neopentyl glycolato)4-(14′-bromo-3′-thia-1′-ketotetradecyl) phenylboronate ester.

[0096] An oven-dried, 500 ml, 3-necked, round-bottomed flask was chargedwith 5.13 grams of the (neopentyl glycolato)4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronate ester and 50 mlof anhydrous dichloromethane. To this solution was added 7.52 grams ofcarbontetrabromide, and the resulting reaction mixture was allowed tostir at 0° C. using an ice bath. A solution of 5.95 grams oftriphenylphosphine dissolved in 10 ml of anhydrous dichloromethane wasadded slowly to the reaction mixture using an addition funnel. Thereaction mixture was stirred at 0° C. and then allowed to warm to roomtemperature slowly. After 16 hours, 20 ml of methanol was added to thereaction mixture. After stirring for 1 hour, the solvent was removed byrotary evaporator. The residue was treated with 200 ml of diethyl etherand stirred for 30 minutes. The mixture was filtered and the solvent wasremoved under reduced pressure. The residue was again treated with etherand the solvent was removed. The resulting residue was flashchromatographed using hexane/ethyl acetate (98/2). After removal of thesolvent, the product was isolated as an off-white solid (yield=4.5grams).

[0097] Step 5.4-(14′-trimethylammonium-3′-thia-1′-keto-tetradecyl)phenylboronic acidchloride.

[0098] A 100 ml, round-bottomed, flask was charged with 500 mg of(neopentyl glycolato) 4-(14′-bromo-3′-thia-1′-ketotetradecyl)phenylboronate ester and 5 ml of ethanol. To thissolution was added 5 ml of 40% aqueous solution of trimethylamine. Thereaction mixture was stirred at 70° C. for 24 hours. After cooling toroom temperature, the solvent was removed under reduced pressure. Theresidue was dissolved in 5 ml of methanol and 20 ml 2N HCl. Afterstirring for 24 hours, the solution was extracted with ethyl acetate(2×100ml) to remove the neopentyl glycol. The aqueous solution wasextracted with chloroform (3×50 ml). The chloroform extracts werecombined and dried over MgSO₄. After filtration, the solvent was removedunder reduced pressure and the residue was dried under vacuum to give300 mg of a gummy solid.

Example 5 Synthesis of (Neopentyl Glycolato)4-(14′-Dimethylamino-3′-Thia-1′-Ketotetradecyl)Phenylboronate Ester

[0099]

[0100] An oven-dried, 250 ml, 3-necked, round-bottomed flask was chargedwith 2.5 grams of the (neopentyl glycolato)4-(14′-bromo-3′-thia-1′-keto)tetradecyl phenylboronate ester (preparedas described in Example 4, step 4) and 25 ml of anhydroustetrahydrofuran (THF). To this mixture was added 8 ml of 2 Mdimethylamine in THF. After stirring at room temperature for 48 hours,the solvent was removed under reduced pressure. The residue was stirredwith 100 ml of 5% aqueous sodium bicarbonate solution for 1 hour and wasthen extracted with ethyl acetate (2×200 ml). After drying overanhydrous sodium sulfate, the solvent was removed under reduced pressureto yield 1.7 grams of the compound as a gummy solid.

Example 6 Synthesis of4-{14′(3″-chlorotrimethylammium)dimethyl-propylammonium--3′-thia-1′-ketotetradecyl}phenylboronic acid chloride

[0101]

[0102] A 100 ml, round-bottomed, flask was charged with 700 mg of(neopentyl glycolato)4-(14′-dimethylamino-3′-thia-1′-ketotetradecyl)phenylboronate ester(prepared as described in Example 5), 400 mg of3-bromopropyltrimethylammonium bromide and 10 ml of ethanol. Thereaction mixture was stirred at 70° C. for 24 hours. After cooling toroom temperature, the solvent was removed under reduced pressure. Theresidue was dissolved in 5 ml of methanol and 40 ml 2 N HCl. Afterstirring for 24 hours, the solution was extracted with ethyl acetate(2×100 ml) to remove neopentyl glycol. The acidified aqueous solutionwas kept in the refrigerator. The precipitated solid was then isolatedby removal of the solvent and dried under vacuum to yield 400 mg of alow melting solid.

Example 7 Synthesis of4-(14′-Sulfato-3′-Thia-1′-Ketotetradecyl)Phenylboronic Acid Sodium Salt

[0103]

[0104] A 100 ml, round-bottomed flask was charged with 3 grams of4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid (prepared asdescribed in Example 4, step 2) and 25 ml of N,N-dimethylformamide(DMF). To this solution was added 1.6 grams of sulfurtrioxide:DMFcomplex and the resulting reaction mixture was stirred at roomtemperature for 24 hours. To the reaction mixture was added a solution 2grams of NaOH dissolved in 100 ml of water:methanol mixture (1:1) andstirred for 1 hour. The solvent was removed under pressure and theresidue was treated with 100 ml of methanol. After stirring for 1 hour,the reaction mixture was filtered. The filtrate was rotary evaporated todryness, yielding 1.5 grams of an off-white solid.

Example 8 Preparation of 4-(11′-Hydroxyundecyl)Carboxyphenylboronic Acid

[0105]

[0106] A mixture of 4-carboxyphenylboronic acid (1.0 grams), potassiumhydrogen carbonate (2.01 g), 11-bromo-1-undecanol, andN,N-dimethylformamide (60 mL) was heated at 60° C. under a nitrogenatmosphere for 18 hours. After the heating period, the mixture wasallowed to cool to room temperature. The mixture was then filtered andthe filtrate was concentrated on a rotary evaporator. The concentratedfiltrate was diluted with ethyl acetate (500 mL) and the ethyl acetatewas washed successively with saturated aqueous sodium bicarbonate (3×300mL), followed by saturated aqueous sodium chloride (300 mL). Afterdrying over sodium sulfate, the ethyl acetate extract was concentratedon a rotary evaporator and dried under reduced pressure to afford 2.2grams of the desired product as a light yellow viscous oil thatsolidified upon standing to a white powder.

[0107] The following compounds were synthesized using similarprocedures:

[0108] from 4-carboxyphenylboronic acid and iodooctadecane;

[0109] from 4-carboxyphenylboronic acid and docosyl methane sulfonate;

[0110] from bromooctadecane and (3-carboxy-5-nitrophenyl)boronic acid;

[0111] from 1-bromodecane and (3-carboxyphenyl)boronic acid;

[0112] from 4-carboxyphenylboronic acid and(4-chloropropyl)dimethyloctadecylammonium bromide; and

[0113] from 4-carboxyphenylboronic acid and pentethyleneglycolmonotosylate.

Example 9 Synthesis of [4-(N,N-Dioctadecylcarbamoyl)Phenyl]Boronic Acid

[0114] Step 1. Synthesis of 2-(4-carboxyphenyl)-1,3-dioxa-2-borinane.

[0115] A mixture of 4-carboxyphenylboronic acid (5.0 grams) and1,3-propanediol (2.5 grams) in toluene (300 mL) was refluxed with aDean-Stark apparatus for 6 hours. After the heating period the reactionsolution was concentrated on a rotary evaporator and dried under reducedpressure to afford 6.39 grams of the desired product as a white solid.

[0116] Step 2. Synthesis of 2-(4-carbonylchloride)-1,3-dioxa-2-borinane.

[0117] To a solution of the above propane diol protected4-carboxyphenylboronic acid (1.0 grams) in chloroform (5 mL) was addedthionyl chloride (3.0 mL) and dimethylformamide (100 microliters). Thesolution was heated to reflux for 2 hours. After the heating period, thereaction solution was allowed to cool to room temperature and wasconcentrated on a rotary evaporator under reduced pressure. To theresidue was added chloroform (8 mL) and the resulting solution wasconcentrated on a rotary evaporator. The addition of chloroform (8 mL)and the concentrating of the solution was repeated twice more. The crudematerial was dried under vacuum to afford 1.09 grams of the desiredproduct as an off-white solid.

[0118] Step 3. Synthesis of [4-(N,N-dioctadecylcarbamoyl)phenyl]boronicacid.

[0119] To a solution of 2-(4-carbonylchloride)- 1,3-dioxa-2-borinane(0.8 grams) in chloroform (30 mL) under nitrogen was addeddioctadecylamine (1.93 grams), triethylamine (1.0 mL), and chloroform(10 mL). The reaction mixture was allowed to stir overnight, after whichit was diluted with chloroform (200 mL). The chloroform solution waswashed in a separatory funnel successively with the following aqueoussolutions: 10% HCl (3×100 mL), saturated sodium bicarbonate (3×100 mL),and saturated sodium chloride (100 mL). The chloroform extract was driedover sodium sulfate. 2.41 grams of crude material was isolated afterfiltration and concentration on a rotary evaporator under reducedpressure. The desired product was purified via column chromatographyover silica gel using a mixture of ethyl acetate and hexane as eluent.

Example 10 Synthesis of4-(13′-Carboxy-3′-Thia-1′-Ketotridecyl)Phenylboronic Acid

[0120]

[0121] A 100-mL, three-necked flask was charged with4-(2′-bromoacetyl)phenyl boronic acid (0.95 g, 3.91 mmol) and 20 mL TEF.The mixture was degassed by bubbling nitrogen through the reactionmixture for about 20 minutes. 11-Mercaptoundecanoic acid (0.9 g, 4.1mmol) was added to the reaction mixture with stirring under nitrogen.Diisopropylethylamine (1.52 g, 2.05 mL, 11.8 mmol) was then added via asyringe over 5 minutes. The reaction mixture was stirred for 72 hoursunder nitrogen at room temperature. The solvent was removed in vacuo,and the residue was partitioned between ethyl acetate (100 mL) and water(100 mL). The organic extract was washed with 1 N hydrochloric acid(3×100 mL), water (100 mL) and brine (100 mL). The organic extract wasdried over magnesium sulfate and then filtered. The filtrate was thenconcentrated in vacuo. The residue was dissolved in about 25 mL of hotethyl acetate. When the mixture was cooled to room temperature, it wasplaced in a freezer. Product crystallized from the solution. The whitecrystalline material was filtered, washed with cold ethyl acetate, anddried in vacuo. 0.93 g (2.45 mmol) of the pure product was obtained.Yield: 62.5%.

Example 11 Phenyl Boronic Acids of the Present Invention InhibitLipolysis In Vitro

[0122] An in vitro assay of pancreatic lipase activity was used tomeasure the efficacy of lipase inhibitory compounds. Porcine pancreaticlipase (23 units/milliliters) was incubated for 4 hours at 37° C. with72 mM triglyceride (as an olive oil/gum arabic emulsion) in 5.5milliliters of a 300 mM BES buffer, pH 7.0, containing 10 mM CaCl₂, 109mM NaCl, and 8 mM sodium taurocholate. The reaction was stopped byacidification with HCl and the lipids were extracted by the methoddisclosed in Folch, et al., J. Biol. Chem. 226:497 (1957) prior toanalysis by HPLC. An aliquot of the chloroform layer was evaporated andreconstituted in hexane, and the sample was analyzed on a WatersAlliance 2690 HPLC with a Sedex 55 Evaporative Light Scattering detectorutilizing a YMC PVA Sil 3×50 millimeter column. The mobile phaseconsisted of hexane and methyl t-butyl ether delivered in a lineargradient at a flow rate of 0.5 milliliters/minute. External standardswere utilized for quantitation of triglycerides, diglycerides, and fattyacids, and the percent lipolysis was determined. For evaluation oflipase inhibitor efficacy, compounds were dissolved in DMSO or anotherappropriate solvent and added directly to the assay mixture prior toincubation. Inhibition was determined relative to a control incubationand IC₅₀ values were calculated from a plot of % inhibition vs.inhibitor concentration. The results are shown in the Table. As can beseen, the boronic acid compounds of the present invention are effectivelipase inhibitors.

Example 12 Phenyl Boronic Acids of the Present Invention InhibitLipolysis In Vivo

[0123] Compounds were evaluated in rats to determine their in vivopotency in inhibiting fat absorption through lipase inhibition. Ratswere acclimated to the facility for approximately 1 week in individualwire-bottom cages and provided a standard chow diet and water adlibitum. Rats were then randomly assigned to groups of 4. They weregavaged at (7-8 AM) with 4 milliliters olive oil emulsified with gumarabic, with or without drug following an 18 hour fast. Test compoundswere dissolved in DMSO or dionized water. Drug solutions were mixedthoroughly in the olive oil emulsion just prior to administration. After8 hours, rats were euthanized with CO₂ and the intestines were removed.The intestinal contents were harvested from the lower half of the smallintestine and the cecum. Contents were placed in separate, pre-weighed,15 milliliters conical screw cap tubes in a (dry ice/ alcohol bath) tomaintain freezing temperature until the final freeze of all samples.Samples were stored at −80° C. until lyophilization.

[0124] Samples were freeze-dried and ground, then analyzed fortriglyceride and fatty acid.

[0125] A 20 milligrams aliquot of each sample was weighed andtransferred to a 15 milliliters conical tube. 3 milliliters of hexanewas added to each tube then it was capped and vortexed for 15 seconds athigh speed. 3 milliliters of 1 N HCl was added then samples weresubjected to wrist-action shaking for 1 hour. Samples were thencentrifuged for 5 minutes at 3500 rpm and the hexane layer wascollected. An aliquot of the hexane layer was diluted in hexane andanalyzed for triglyceride, diglyceride and fatty acid by HPLC asdescribed above.

[0126] The data was expressed as follows. The milligrams of intestinalcontents that were extracted and the total number of milligramscollected were recorded. The milligrams/milliliters values obtained fromthe HPLC analysis were entered. The individual lipid components werecalculated and expressed as total milligrams recovered. Dose units areexpressed as the milligrams of drug per gram of oil administered to eachrat. The ED₅₀'s were determined by extrapolating the dose value at halfthe maximum obtainable triglyceride recoverable in the assay. Theresults are shown in the Table. As can be seen, the boronic acidcompounds of the present invention are effective lipase inhibitors invivo. TABLE Inhibition of in vitro and in vivo lipolysis In Vitro InVivo In Vivo Pancreatic Infusion Infusion Lipase Assay Assay in Assay inIC₅₀ Rats ED₅₀ Rats Ed₅₀ (μg/g fat) (mg/g fat) (mg/kg body wt) TestCompound or estimate or estimate or estimate 4-(14′-trimethylammo- 6.4 860 nium-3′-thia-1′-keto- tetradecyl)-phenyl- boronic acid bromide4-(14′-trimethylammo- 1.8 2 15 nium-3′-thia-1′-keto-tridecyl)-3-fluorophenyl- boronic acid bromide 4-(14′-triethylammo- 1111 82.5 nium-3′-thia-1′-keto- tetradecyl)-3-phenyl- boronic acid bromide

[0127] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound represented by the followingstructural formula:

and pharmaceutically acceptable salts thereof, wherein: Z and Z′ areindependently —O—, —NH— or —S—; Ar is a substituted or unsubstitutedaryl group; X is an electron withdrawing group; R is a substituted orunsubstituted straight chained hydrocarbyl group optionally comprisingone or more amine, ammonium, ether, thioether or phenylene linkinggroups; Y is —H, an amine, —[NH—(CH₂)_(q)]_(r)—NH₂, halogen, —CF₃,thiol, ammonium, alcohol, —COOH, —SO₃H, —OSO₃H or phosphonium groupcovalently bonded to the terminal position of R, provided that when Y is—H and R is a straight chained hydrocarbyl group, then R has from 1 to30 carbon atoms, and provided that each —NH— in —[NH—(CH₂)_(q)]_(r)—NH₂is optionally N-alkylated or N,N-dialkylated and —NH₂ in—[NH—(CH₂)_(q)]_(r)—NH₂ is optionally N-alkylated, N,N-dialkylated orN,N,N-trialkylated; q is an integer from 2 to about 10; r is an integerfrom 1 to about 5; R₁ and R₁′ are independently —H, an aliphatic group,a substituted aliphatic group, an aryl group or a substituted aryl groupor, taken together, are a C2-C5 substituted or unsubstituted alkylenegroup optionally comprising an amine linking group [—N⁺(R^(1a))—]; andR^(1a) is —H, alkyl, substituted alkyl, phenyl or substituted phenyl. 2.The compound of claim 1 wherein Z and Z′ are both —O—.
 3. The compoundof claim 2 wherein Ar is a substituted or unsubstituted phenyl group. 4.The compound of claim 3 wherein R¹ and R₁′ are both —H.
 5. The compoundof claim 4 wherein X is —CZ₂—, —CHZ—, —COO—, —CONR^(1b)—, —CO—, —S(O)—,—S(O)₂O— or —SO₂—; R^(1b) is —H, alkyl or substituted alkyl; and Z is ahalogen and —X—R—Y is para to —B(OH)₂.
 6. The compound of claim 5wherein X is —CZ₂—, —CHZ—, —COO—, —CONR^(1b)—, —CO— or —SO₂—.
 7. Thecompound of claim 6 wherein X is —CO—, R is a substituted orunsubstituted straight chained hydrocarbyl group comprising one or moreamine or ammonium linking groups, and Y is —H, an amine or an ammoniumgroup.
 8. The compound of claim 7 wherein R is an unsubstituted straightchained hydrocarbyl group comprising one ammonium linking group; Y is—H; and Phenyl Ring A is substituted with one or more groups R₂, whereineach R₂ is an electron withdrawing group and is independently selected.9. A compound represented by the following structural formula:

and pharmaceutically acceptable salts thereof, wherein: Phenyl Ring A issubstituted or unsubstituted; and R is a substituted or unsubstitutedstraight chained hydrocarbyl group optionally comprising one or moreether, thioether, phenylene, amine, or ammonium linking groups; and Y isan amine or ammonium group covalently bonded to the terminal position ofR.
 10. The compound of claim 9 wherein R is—CH₂—O[—(CH₂)_(p)O]_(m)—(CH₂)_(p)— or —CH₂—S[—(CH₂)_(p)O]—(CH₂)_(p)—; pis 2 or 3; and m is an integer from 1-8.
 11. The compound of claim 9wherein R is a straight chained hydrocarbyl group optionally comprisingone or more ether or thioether linking groups.
 12. The compound of claim11 wherein Phenyl Ring A is optionally substituted with one or moregroups R₂, wherein each R₂ is an electron withdrawing group and isindependently selected.
 13. The compound of claim 12 wherein R is anunsubstituted straight chained hydrocarbyl group optionally comprisingone ether or one thioether linking group and Y is a trialkylammmoniumgroup.
 14. The compound of claim 12 wherein Phenyl Ring A is substitutedwith one or two groups R₂ and each R₂ is —F.
 15. A compound representedby a structural formula selected from:

and pharmaceutically acceptable salts thereof, wherein Y is atrialkylammonium group; n is an integer from about 6 to about 30; andPhenyl Ring A is substituted with one or two groups R₂, wherein each R₂is an electron withdrawing group and is independently selected.
 16. Thecompound of claim 15 wherein Y is a trimethylammonium group and PhenylRing A is substituted with up to two fluorine groups.
 17. The compoundof claim 16 wherein the compound is represented by the followingstructural formula:

wherein R₃ is —H or —F.
 18. A compound represented by the followingstructural formula:

and pharmaceutically acceptable salts thereof, wherein R₃ is —H or —F; nis an integer from about 6 to about 15; and Y is a trimethyl ammoniumgroup.
 19. A method of treating a subject for obesity comprising thestep of administering to the subject an effective amount of a compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salts thereof, wherein: Z and Z′ areindependently —O—, —NH— or —S—; Ar is a substituted or unsubstitutedaryl group; X is an electron withdrawing group; R is a substituted orunsubstituted straight chained hydrocarbyl group optionally comprisingone or more amine, ammonium, ether, thioether or phenylene linkinggroups; Y is —H, an amine, —[NH—(CH₂)_(q)]_(r)NH₂, halogen, —CF₃, thiol,ammonium, alcohol, —COOH, —SO₃H, —OSO₃H or phosphonium group covalentlybonded to the terminal position of R, provided that when Y is —H and Ris a straight chained hydrocarbyl group, then R has from 1 to 30 carbonatoms, and provided that each —NH— in —[NH—(CH₂)_(q)]_(r)NH₂ isoptionally N-alkylated or N,N-dialkylated and —NH₂ in—[NH—(CH₂)_(q)]_(r)NH₂ is optionally N-alkylated, N,N-dialkylated orN,N,N-trialkylated.; q is an integer from 2 to about 10; r is an integerfrom 1 to about 5; R₁ and R₁′ are independently —H, an aliphatic group,a substituted aliphatic group, an aryl group or a substituted aryl groupor, taken together, are a C2-C5 substituted or unsubstituted alkylenegroup optionally comprising an amine linking group [—N⁺(R^(1a))—]; andR^(1a) is —H, alkyl, substituted alkyl, phenyl or substituted phenyl 20.The method of claim 19 provided that when Y is -H and R is a straightchained hydrocarbyl group, then R has from 4 to 30 carbon atoms.
 21. Themethod of claim 20 wherein Z and Z′ are both —O—.
 22. The method ofclaim 21 wherein Ar is a substituted or unsubsituted phenyl group. 23.The method of claim 22 wherein R₁ and R₁′ are both —H.
 24. The method ofclaim 23 wherein X is —CZ₂—, —CHZ—, —COO—, —CONR^(1b)—, —CO—, —S(O)—,—S(O)₂O— or —SO₂—; R^(1b) is —H, alkyl or substituted alkyl; Z is ahalogen and —X—R—Y is para to —B(OH)₂.
 25. The method of claim 24wherein X is —CZ₂—, —CHZ—, —COO—, —CONR^(1b)—, —CO—, or —SO₂—;
 26. Themethod of claim 24 wherein X is —CO—, R is a substituted orunsubstituted straight chained hydrocarbyl group comprising one or moreamine or ammonium linking groups, and Y is —H, an amine or an ammoniumgroup.
 27. The method of claim 26 wherein R is an unsubstituted straightchained hydrocarbyl group comprising one ammonium linking group; Y is—H; and Phenyl Ring A is substituted with one or more groups R₂, whereineach R₂ is an electron withdrawing group and is independently selected.28. A method of inhibiting the uptake of fat in the gastrointestinaltract of a subject in need of such treatment, comprising the step ofadministering to the subject an effective amount of a compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: Phenyl Ring A issubstituted or unsubstituted; and R is a substituted or unsubstitutedstraight chained hydrocarbyl group optionally comprising one or moreether, thioether, phenylene, amine, or ammonium linking groups; and Y isan amine or ammonium group covalently bonded to the terminal position ofR.
 29. The method of claim 28 wherein the subject is being treated forobesity.
 30. The method of claim 29 wherein R is—CH₂—O[—(CH₂)_(p)O]_(m)—(CH₂)_(p)— or—CH₂—S[—(CH₂)_(p)O]_(m)—(CH₂)_(p)—; p is 2 or 3; and m is an integerfrom 1-8.
 31. The method of claim 30 wherein R is a straight chainedhydrocarbyl group optionally comprising one or more ether or thioetherlinking groups
 32. The method of claim 31 wherein Phenyl Ring A isoptionally substituted with one or more groups R₂, wherein each R₂ is anelectron withdrawing group and is independently selected.
 33. The methodof claim 32 wherein R is an unsubstituted straight chained hydrocarbylgroup optionally comprising one ether or one thioether linking group andY is a trialkylammmonium group.
 34. The method of claim 28 whereinPhenyl Ring A is substituted with one or two groups R₂ and each R₂ is—F.
 35. A method of treating a subject for obesity comprising the stepof administering to the subject an effective amount of a compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein Y is atrialkylammonium group; n is an integer from about 6 to about 30; andPhenyl Ring A is substituted with one or two groups R₂, wherein each R₂is an electron withdrawing group and is independently selected.
 36. Themethod of claim 35 wherein Y is a trimethylammonium group and PhenylRing A is substituted with up to two fluorine groups.
 37. The method ofclaim 36 wherein the compound is represented by the following structuralformula:

wherein R₃ is —H or —F.
 38. A method of treating a subject for obesitycomprising the step of administering to the subject an effective amountof a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R₃ is —H or —F; nis an integer from about 6 to about 15; and Y is a trimethylammoniumgroup.
 39. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or diluent and a compound represented by thefollowing structural formula:

and pharmaceutically acceptable salts thereof, wherein: Z and Z′ areindependently —O—, —NH— or —S—; Ar is a substituted or unsubstitutedaryl group; X is an electron withdrawing group; R is a substituted orunsubstituted straight chained hydrocarbyl group optionally comprisingone or more amine, ammonium, ether, thioether or phenylene linkinggroups; Y is —H, an amine, halogen, —[NH—(CH₂)_(q)]_(r)—NH₂, —CF₃,thiol, ammonium, alcohol, —COOH, —SO₃H, —OSO₃H or phosphonium groupcovalently bonded to the terminal position of R, provided that when Y is—H and R is a straight chained hydrocarbyl group, then R has from 1 to30 carbon atoms, and provided that each —NH— in —[NH—(CH₂)_(q)]_(r)NH₂is optionally N-alkylated or N,N-dialkylated and —NH₂ in—[NH—(CH₂)_(q)]_(r)—NH₂ is optionally N-alkylated, N,N-dialkylated orN,N,N-trialkylated.; q is an integer from 2 to about 10; r is an integerfrom 1 to about 5; R₁ and R₁′ are independently —H, an aliphatic group,a substituted aliphatic group, an aryl group or a substituted aryl groupor, taken together, are a C2-C5 substituted or unsubstituted alkylenegroup optionally comprising an amine linking group [—N⁺(R^(1a))—]; andR^(1a) is —H, alkyl, substituted alkyl, phenyl or substituted phenyl.40. The pharmaceutical composition of claim 39 provided that when Y is—H and R is a straight chained hydrocarbyl group, then R has from 4 to30 carbon atoms.
 41. The pharmaceutical composition of claim 40 whereinZ and Z′ are both —O—.
 42. The pharmaceutical composition of claim 41wherein Ar is a substituted or unsubstituted phenyl group.
 43. Thepharmaceutical composition of claim 42 wherein R₁ and R₁′ are both —H.44. The pharmaceutical composition of claim 43 wherein X is —CZ₂—,—CHZ—, —COO—, —CONR^(1b)—, —CO—, —S(O)—, —S(O)₂O— or —SO₂—; R^(1b) is—H, alkyl or substituted alkyl; Z is a halogen and —X—R—Y is para to—B(OH)₂.
 45. The pharmaceutical composition of claim 44 wherein X is—CZ₂—, —CHZ—, —COO—, —CONR^(1b)—, —CO— or —SO₂—.
 46. The pharmaceuticalcomposition of claim 41 wherein X is —CO—, R is a substituted orunsubstituted straight chained hydrocarbyl group comprising one or moreamine or ammonium linking groups, and Y is —H, an amine or an ammoniumgroup.
 47. The pharmaceutical composition of claim 46 wherein R is anunsubstituted straight chained hydrocarbyl group comprising one ammoniumlinking group; Y is —H; and Phenyl Ring A is substituted with one ormore groups R₂, wherein each R₂ is an electron withdrawing group and isindependently selected.
 48. A pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and a compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: Phenyl Ring A issubstituted or unsubstituted; and R is a substituted or unsubstitutedstraight chained hydrocarbyl group optionally comprising one or moreether, thioether, phenylene, amine, or ammonium linking groups; and Y isan amine or ammonium group covalently bond to the terminal position ofR.
 49. The pharmaceutical composition of claim 48 wherein R is—CH₂—O[—(CH₂)_(p)O]_(m)—(CH₂)_(p)— or—CH₂—S[—(CH₂)_(p)O]_(m)—(CH₂)_(p)—; p is 2 or 3; and m is an integerfrom 1-8.
 50. The pharmaceutical composition of claim 48 wherein R is astraight chained hydrocarbyl group optionally comprising one or moreether or thioether linking groups.
 51. The pharmaceutical composition ofclaim 50 wherein Phenyl Ring A is optionally substituted with one ormore groups R₂, wherein each R₂ is an electron withdrawing group and isindependently selected.
 52. The pharmaceutical composition of claim 51wherein R is an unsubstituted straight chained hydrocarbyl groupoptionally comprising one ether or one thioether linking group and Y isa trialkylammmonium group.
 53. The pharmaceutical composition of claim52 wherein Phenyl Ring A is substituted with one or two groups R₂ andeach R₂ is —F.
 54. A pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and a compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein Y is atrialkylammonium group; n is an integer from about 6 to about 30; andPhenyl Ring A is substituted with one or two groups R₂, wherein each R₂is an electron withdrawing group and is independently selected.
 55. Thepharmaceutical composition of claim 54 wherein Y is a trimethylammoniumgroup and Phenyl Ring A is substituted with up to two fluorine groups.56. The pharmaceutical composition of claim 55 wherein the compound isrepresented by the following structural formula:

wherein R₃ is —H or —F.
 57. A pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and a compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R₃ is —H or —F; nis an integer from about 6 to about 15; and Y is a trimethyl ammoniumgroup.